The cellular redox reactions of coenzymes NAD+, NADH and NADP+, NADPH are well known (Pollak, N. et al, Biochem. J., 402: 205-218 (2007)). It is known that NAD+ plays an important role in apoptosis (Gendron, M. C. et al., Biochem. J., 353: 357 (2001)), calcium mobilization (Guse, A. H. et al., J. Biol. Chem., 280: 15952 (2005)), cell proliferation (Bruzzone, S. et al., Biochem. J., 375: 395 (2003)), aging (Blasco, M. A., Nat. Rev. Genet., 6: 611 (2005)), gene expression (Girolamo, M. D. et al., J. Biol. Chem., 282: 16441 (2007); Sauve, A. A.; Schramm, V. L., Biochemistry, 42: 9249 (2003); Michan, S. et al., Biochem. J., 404: 1 (2007); Nakano, T. et al., Proc. Natl. Acad. Sci. U.S.A., 103: 13652 (2006); Culver, G. M. et al., J. Biol. Chem., 272: 13203 (1997); Berger, F. et al., Proc. Natl. Acad. Sci. U.S.A., 104: 3765 (2007)), immune system modulation (Song, E. K. et al., Biochem. Biophys. Res. Commun., 367: 156 (2008); Seman, M. et al., Immunity, 19: 571 (2003)), energy metabolism and metabolic regulation. Mono and poly (ADP-ribose) polymerases use NAD+as substrate for protein covalent modifications (Ziegler, M., Eur. J. Biochem., 267: 1550 (2000); Guarente, L. et al., Cell, 120: 473 (2005); Marmorstein, R., Biochem. Soc. Trans., 32: 904 (2004); Magni, G. et al., Cell. Mol. Life Sci., 61: 19 (2004); Araki, T. et al., Science, 305: 1010 (2004)). NAD+ can be synthesized enzymatically (Suhadolnik, R. J. et al., Biol. Chem., 252: 4125 (1977)) and chemically (Jeck, R. et al., Eds., Academic: New York, 66: 62 (1979)) from various precursors of vitamin B3 (nicotinic acid (NA), nicotinamide (Nam), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN)) and from tryptophan. NAD+-tutilizing reactions liberate nicotinamide, which is recycled to form NMN from nicotinamide and 5-phosphoribosyl pyrophosphate using the enzyme nicotinamide phosphoribosyltransferase. The synthesized NMN reacts with ATP and is converted to NAD+ by nicotinamide mononucleotide adenyltransferase (NMNAT).
Increasing interest in precursors that can be administrated to increase physiological NAD+ provides impetus to develop efficient and practical syntheses of precursors such as NR and NMN. A highly efficient chemical synthesis of NR has been developed (Yang, T. et al., J. Med. Chem., 50: 6458 (2007)). Literature indicates that aside from enzymatic reactions there are few different chemical methods for the synthesis of nicotinamide mononucleotide and derivatives (Burgos, E. S. et al., Biochemistry, 47: 11086 (2008); Rozenberg, A. et al., J. Org. Chem., 73: 9314 (2008)). Existing synthetic strategies involve complicated intermediates, and isolation of NMN is difficult in good yields. Moreover, enzymatic reactions are typically limited to small scale chemical synthesis and are expensive, and thus are less immediately scalable to multigram or kilogram scale.
Thus, there is an unmet need for an improved process for the preparation of nicotinamide mononucleotide.